Chronic pain is a public health epidemic in the U.S., affecting more than 116 million people and costing greater than $600 billion per year to treat. Spinal cord injury (SCI) results not only in debilitating motor, sensory and cognitive deficits, bu also in a chronic, severe and often unrelenting pain that is largely resistant to conventional treatments (SCI-PAIN). Occurring in as many as 85% of SCI patients, pain starts weeks or months after the original insult, and includes increased pain with noxious stimulation (hyperalgesia), pain in response to previously innocuous stimuli (allodynia), and spontaneous pain. This unremitting pain can be diffuse, bilateral, and usually extends to locations caudal to the spinal injury. The delayed expression of SCI- PAIN and the diffuse localization of painful symptoms suggest that the pathophysiology reflects more than the direct effects at the denervated spinal segments. Indeed, these features of SCI-PAIN strongly suggest the occurrence of maladaptive plasticity in the spinal dorsal horn. An important focus for drug development has been to identify new therapeutic targets/molecules that participate in the spinal cord plasticity associated with the persistence of SCI-PAIN. One promising new therapeutic target, Brain-derived Neurotrophic Factor (BDNF), modulates nociception in the spinal cord. BDNF exerts its effects on nociceptive processing by binding to its full-length, cell surface receptor tropomyosin-related kinase B (trkB.FL) and initiating intracellular signaling. In addition to trkB.FL, the trkB locus also produces a widely-expressed alternatively-spliced truncated isoform, trkB.T1, but the function of this receptor isoform in nociception is largely unknown. TrkB.T1 is upregulated in several non-pain and pain related pathological states and we have reported that the genetic deletion of this receptor in mouse provides significant protection from the development of thermal hyperalgesia and mechanical allodynia across several models of chronic pain. Crucial to this proposal, we have preliminary data showing that trkB.T1 deletion results in significantly improved locomoter recovery and reduced allodynia in a moderate contusion injury mouse model of SCI developed by our group. We conducted differential gene expression studies to examine the potential transcriptional mechanisms regulating these improvements, and found that upregulation of key cell cycle genes correlating with neuronal apoptosis after experimental SCI, are not upregulated in the trkB.T1 null spinal cord. These results suggest that trkB.T1 may be an exciting new molecular target. In this study, we will systematically evaluate, using in vitro and in vivo approaches, whether trkB.T1 regulation of cell cycle genes contributes to SCI-PAIN and determine whether targeting cell cycle genes or trkB.T1, separately or in combination for enhanced effectiveness, can be utilized to develop novel therapeutic interventions to reduce or ameliorate SCI-PAIN.